N-system amino acid transport in liver and skeletal muscle mediates glutamine and histidine uptake via a Na-dependent process. We have recently identified this transporter at the blood-CSF barrier (choroid plexus). This transporter, which also appears present at the blood-brain barrier, may aid in controlling the concentration of these two important amino acids in the brain. Increased cerebral glutamine appears to be involved in the genesis of hepatic encephalopathy and we hypothesize that glutamine is the form by which brain glutamate is lost during cerebral ischemia. Histidine, an essential amino acid, is the principal source of histamine, a potential mediator of brain injury in hepatic encephalopathy and cerebral ischemia. The aims of this proposal are: 1) Determine the role of N-system transport in glutamine and histidine movement at the blood-brain and blood-CSF barriers. 2) Examine its role in controlling brain glutamine in hepatic encephalopathy and to investigate whether competition between glutamine and histidine for this transporter may lead to increased histidine and thus histamine in the brain, with the latter resulting in brain injury. 3) Examine whether glutamine efflux via the N-system transporter participates in the clearance of glutamate from the brain during cerebral ischemia. This may lessen brain swelling by removing both an idiogenic osmole and an excitatory amino acid but it could also lead to histamine release and brain injury. These specific aims will be addressed by a combination of in vivo and in vitro experiments in control, hyperammonemic, ischemic and hypo-osmotic rats. The role of N-system transport in glutamine and histidine efflux from the brain will be examined using isolated choroid plexuses, vesicles from cerebral microvessels and by measuring arterio-venous differences. The potential role for this transporter in influx to the brain will be examined by in situ brain perfusion. Stroke and liver disease are major causes of mortality in the U.S.A. A greater knowledge of cerebral glutamine and histidine may aid in our understanding of the progression of these diseases and lead to new therapies.